OP0047 IMPAIRED JAK-STAT PATHWAY IN PATIENTS WITH PYODERMA GANGRENOSUM
Authors: T. Demirci Yildirim, A. Kahraman Akkalp, A. Köken Avşar, F. Onen, S. Akar, I. Sari
Journal: Annals of the Rheumatic Diseases (2022)

Background Pyoderma gangrenosum (PG) is an inflammatory disease with an unknown etiology. Currently there is an unmet need in the of PG. In recent years, JAK/STAT pathway have been shown to have an important role in the etiology of inflammatory conditions particularly in the field of dermato-rheumatology. However, current data on JAK/STAT pathway in PG is significantly limited. Objectives Herein we aimed to investigate the JAK/STAT signaling pathway in the skin biopsies of PG patients and compared with psoriasis (PSO) and healthy subjects (HS). Methods 31 patients with PG, 35 patients with PSO and 26 HS were included. Immunohistochemical methods were used to evaluate the expression of JAK1, JAK2, JAK3, Tyrosine Kinase 2 (TYK2), STAT1, STAT3, STAT4, STAT5, and STAT6. In the dermis the staining intensity was recorded as ‘positive’ or ‘negative. The epidermal part is divided into cytoplasmatic and nuclear parts and staining intensity recorded by semi-quantitively as follows: negative, mildly positive, moderately positive and strongly positive. Results In total, there were 92 biopsies. Dermal staining was significant for all the JAK/STAT proteins for patients with PG and PSO when compared to HS. On the other hand, there were no differences in the staining patterns of PG and PSO. For the investigation of cytoplasmic parts of epidermis JAK1, STAT3, and STAT4 were highly expressed in the PG and PSO, STAT6, and TYK2 were only significantly overexpressed in psoriasis. JAK3 was overexpressed in healthy skin, PG and psoriasis. The assessment of the nuclear part of epidermis TYK2 and STAT3 were highly expressed in the PG and PSO. JAK1 was overexpressed in PG versus PSO in cytoplasmic parts of the epidermis (p&lt;0.001). TYK2 and STAT6 were highly expressed in the PSO versus PG in cytoplasmic parts of the epidermis (p = 0.024, p&lt;0.001). In the investigation of nuclear parts of epidermis STAT1, STAT6 were highly expressed in the PSO versus PG. The summary of the findings is given in Table 1. Table 1. Summary of the findings Healthy Subjects (n=26) Pyoderma Gangrenosum (n=31) Psoriasis (n=35) Age, mean ± SD 60,3 ± 18,3 58,1 ± 16,1 46,5 ± 18,4 Women/men (% ) 14/12 18/13 15/20 Dermal staining JAK1 Positive, n (%) 0 7 (22.6)* 3 (8.5) JAK3 Positive, n (%) 0 27 (87)* 31 (88.5)** TYK2 Positive, n (%) 0 31 (100)* 34 (97.2)** STAT1 Positive, n (%) 0 20 (64.5)* 27 (77.1)** STAT3 Positive, n (%) 0 29 (93.6)* 1 (2.8) STAT4 Positive, n (%) 0 7 (22.6)* 11 (31.4)** STAT5 Positive, n (%) 0 9 (29.3) 27 (77.1)** STAT6 Positive, n (%) 0 3 (9.7) 33 (94.3)** cytoplasmic parts of epidermis JAK1 Negative, n (%) 0 1 0 Mildly positive, n (%) 0 0 0 Moderately positive, n (%) 23 (88.4) 6 (19.4) 24 (68.5) Strongly positive, n (%) 3 (11.5) 24 (77.4)* 11 (31.5)** TYK2 Negative, n (%) 0 (0) 1 (3.2) 2 (5.7) Mildly positive, n (%) 0 (0) 4 (12.9) 1 (2.8) Moderately positive, n (%) 18 (69.2) 18 (58.1) 11 (31.4) Strongly positive, n (%) 8 (30.8) 8 (25.8) 21 (60)** STAT3 Negative, n (%) 0 1 (3.2) 0 Mildly positive, n (%) 0 1 (3.2) 0 Moderately positive, n (%) 12 (46.1) 1 (3.2) 1 (2.8) Strongly positive, n (%) 14 (53.9) 28 (90.4)* 34 (97.2)** STAT4 Negative, n (%) 0 1 (3.2) 0 Mildly positive, n (%) 0 1 (3.2) 0 Moderately positive, n (%) 12 (46.1) 3 (9.7) 6 (17.1) Strongly positive, n (%) 14 (53.9) 26 (83.9) * 29 (82.9) ** STAT6 Negative, n (%) 18 (69,2%) 15 (48,4%) 1 (2,8%) Mildly positive, n (%) 8 (30,8%) 16 (51,6%) 0 Moderately positive, n (%) 0 0 20 (57,2%) Strongly positive, n (%) 0 0 14 (40%)** nuclear part of epidermis TYK2 Negative, n (%) 22 (84,6%) 1 (3,2%) 2 (5,7%) Mildly positive, n (%) 4 (15,4%) 10 (32.2%) 6 (17,1%) Strongly positive, n (%) 0 20 (64,6%)* 27 (77,2%)** STAT3 Negative, n (%) 0 1 (3,2%) 0 Mildly positive, n (%) 16 (61,5%) 2 (6,5%) 5 (14,3%) Strongly positive, n (%) 10 (38,5%) 28 (90,4%)* 30 (85,7%)** Data were shown mean±SD and n (%), *= significant expression HS vs PG, **= significant expression HS vs PSO. Conclusion In this study, the JAK/STAT inflammatory pathway is significantly activated in PG patients which is adding up new information to the current literature. Considering the unmet need in PG targeting of this pathway could be beneficial for the treatment of refractory PG. Disclosure of Interests None declared.